@article {Balle202000664, author = {Daniel P Ball and Cornelius Y Taabazuing and Andrew R Griswold and Elizabeth L Orth and Sahana D Rao and Ilana B Kotliar and Lauren E Vostal and Darren C Johnson and Daniel A Bachovchin}, title = {Caspase-1 interdomain linker cleavage is required for pyroptosis}, volume = {3}, number = {3}, elocation-id = {e202000664}, year = {2020}, doi = {10.26508/lsa.202000664}, publisher = {Life Science Alliance}, abstract = {Pathogen-related signals induce a number of cytosolic pattern-recognition receptors (PRRs) to form canonical inflammasomes, which activate pro-caspase-1 and trigger pyroptotic cell death. All well-studied inflammasome-forming PRRs oligomerize with the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) to generate a large structure in the cytosol, which induces the dimerization, autoproteolysis, and activation of the pro-caspase-1 zymogen. However, several PRRs can also directly interact with pro-caspase-1 without ASC, forming smaller {\textquotedblleft}ASC-independent{\textquotedblright} inflammasomes. It is currently thought that little, if any, pro-caspase-1 autoproteolysis occurs during, and is not required for, ASC-independent inflammasome signaling. Here, we show that the related human PRRs NLRP1 and CARD8 exclusively form ASC-dependent and ASC-independent inflammasomes, respectively, identifying CARD8 as the first canonical inflammasome-forming PRR that does not form an ASC-containing signaling platform. Despite their different structures, we discovered that both the NLRP1 and CARD8 inflammasomes require pro-caspase-1 autoproteolysis between the small and large catalytic subunits to induce pyroptosis. Thus, pro-caspase-1 self-cleavage is a required regulatory step for pyroptosis induced by human canonical inflammasomes.}, URL = {https://www.life-science-alliance.org/content/3/3/e202000664}, eprint = {https://www.life-science-alliance.org/content/3/3/e202000664.full.pdf}, journal = {Life Science Alliance} }